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Vaccination against influenza with an influenza vaccine is often recommended for high-risk groups, such as children and the elderly, or in people who have asthma, diabetes, heart disease, or are immuno-compromised. Influenza vaccines can be produced in several ways; the most common method is to grow the virus in fertilized hen eggs. After purification, the virus is inactivated (for example, by treatment with detergent to produce an inactivated-virus vaccine. Alternatively, the virus can be grown in eggs until it loses virulence and the avirulent virus given as a live vaccine. The effectiveness of these influenza vaccines are variable. Due to the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a few years. Every year, the World Health Organization predicts which strains of the virus are most likely to be circulating in the next year, allowing pharmaceutical companies to develop vaccines that will provide the best immunity against these strains. Vaccines have also been developed to protect poultry from avian influenza. These vaccines can be effective against multiple strains and are used either as part of a preventative strategy, or combined with culling in attempts to eradicate outbreaks.

It is possible to get vaccinated and still get influenza. The vaccine is reformulated each season for a few specific flu strains but cannot possibly include all the strains actively infecting people in the world for that season. It takes about six months for the manufacturers to formulate and produce the millions of doses required to deal with the seasonal epidemics; occasionally, a new or overlooked strain becomes prominent during that time and infects people although they have been vaccinated (as by the H3N2 Fujian flu in the 2003–2004 flu season). It is also possible to get infected just before vaccination and get sick with the very strain that the vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective.

Figure 1. Vaccination against influenza virus.

The 2006–2007 season was the first in which the CDC had recommended that children younger than 59 months receive the annual influenza vaccine. Vaccines can cause the immune system to react as if the body were actually being infected, and general infection symptoms (many cold and flu symptoms are just general infection symptoms) can appear, though these symptoms are usually not as severe or long-lasting as influenza. The most dangerous side effect is a severe allergic reaction to either the virus material itself or residues from the hen eggs used to grow the influenza; however, these reactions are extremely rare.

In addition to vaccination against seasonal influenza, researchers are working to develop a vaccine against a possible influenza pandemic. The rapid development, production, and distribution of pandemic influenza vaccines could potentially save millions of lives during an influenza pandemic. Due to the short time frame between identification of a pandemic strain and need for vaccination, researchers are looking at non-egg-based options for vaccine production. Live attenuated (egg-based or cell-based) technology and recombinant technologies (proteins and virus-like particles) could provide better "real-time" access and be produced more affordably, thereby increasing access for people living in low- and moderate-income countries, where an influenza pandemic may likely originate. As of July 2009, more than 70 known clinical trials have been completed or are ongoing for pandemic influenza vaccines. In September 2009, the US Food and Drug Administration approved four vaccines against the 2009 H1N1 influenza virus (the current pandemic strain), and expect the initial vaccine lots to be available within the following month.

An influenza epidemic emerges during each winter's flu season. Each year there are two flu seasons due to the occurrence of influenza at different times in the Northern and Southern Hemispheres. Tens of thousands of Americans die in a typical year, but there are notable variations from year to year. In 2010 the CDC in the United States changed the way it reports the 30-year estimates for deaths from influenza. Now they are reported as a range from a low of about 3,300 deaths to a high of 49,000 per year over the past 30 years.

Worldwide, seasonal influenza kills an estimated 250,000 to 500,000 people each year. The majority of deaths in the industrialized world occur in adults age of 65 and over. A review at the NIAID division of the NIH in 2008 concluded that "Seasonal influenza causes more than 200,000 hospitalizations and 41,000 deaths in the U.S. every year, and is the seventh leading cause of death in the U.S." The economic costs in the U.S. have been estimated at over $80 billion. The number of annual influenza-related hospitalizations is many times the number of deaths. "The high costs of hospitalizing young children for influenza creates a significant economic burden in the United States, underscoring the importance of preventive flu shots for children and the people with whom they have regular contact..."

In the United States, the CDC recommends to clinicians that vaccination is especially important for people at higher risk of serious influenza complications or people who live with or care for people at higher risk for serious complications. Vaccination against influenza is also thought to be important for members of high-risk groups who would be likely to suffer complications from influenza, for example pregnant women and children and teenagers from six months to 18 years of age.

In expanding the new upper age limit to 18 years, the aim is to reduce both the time children and parents lose from visits to pediatricians and missing school and the need for antibiotics for complications An added expected benefit would be indirect — to reduce the number of influenza cases among parents and other household members, and possibly spread to the general community.

Vaccination of school-age children has a strong protective effect on the adults and elderly with whom the children are in contact. Children born to mothers who received flu vaccination while pregnant are strongly protected from having to be hospitalized with the flu. "The effectiveness of influenza vaccine given to mothers during pregnancy in preventing hospitalization among their infants, adjusted for potential confounders, was 91.5%".

Vaccination has been shown highly effective in health care workers, with minimal adverse effects. In a study of forty matched nursing homes, staff influenza vaccination rates were 69.9% in the vaccination arm of versus 31.8% in the control arm. The vaccinated staff experienced a 42% reduction in sick leave from work (P=.03). A review of eighteen studies likewise found a strong net benefit to health care workers. Only two of these eighteen studies also included an assessment of patient mortality relative to staff influenza vaccine. Both studies including this assessment found that higher rates of health care worker vaccination correlated with reduced patient deaths.

In the event of exposure to a pandemic influenza virus, seasonal flu vaccine may also offer some protection against both the H5N1-type (avian influenza) H5N1 infection and the 2009 flu pandemic (the H1N1 "swine flu.").